Tachykinin is a general name for a group of neuropeptides, and there have been known substance P(SP), neurokinin-A, and neurokinin-B in mammals. These peptides are known to exhibit a various kinds of biological activities by binding their corresponding receptors which exist in vivo (neurokinin-1, neurokinin-2, neurokinin-3). Among them, SP is one of those which have the longest history in the neuropeptides, and have been studied in detail. Its existence was confirmed in an extract of horse intestinal tube in 1931, and it was a peptide comprising 11 amino acids, whose structure was determined in 1971.
SP exists widely in peripheral nervous system, and it has physiological activities such as vasodilation action, vascular permeability promoting action, smooth muscle contracting action, hypertarachia (neuronal excitement) action, salivation action, diuretic action, immunological action, etc., as well as a function of neurotransmitter of the primary sensory neuron. Specifically, it is known that SP released from the terminus of posterior horn of spinal cord upon pain impulse transfers pain information to the secondary neuron, and that SP released from the peripheral terminus induces an inflammatory reaction in the receptor. From these facts, SP is considered to be involved in various diseases (for example, pain, inflammation, allergy, thamuria, incontinence of urine, respiratory disease, mental illuness, depression, uneasiness, emesis, etc.), and also, SP is considered to be involved in Alzheimer type dementia (Review: Physiological Reviews, vol. 73, pp. 229–308 (published in 1993), Journal of Autonomic Pharmacology, vol. 13, pp. 23–93 (published in 1993)).
As a compound having a SP receptor antagonistic action, there are disclosed azabicyclo[2.2.1]heptan-3-amine derivative, etc. in Japanese Provisional Patent Publication No. Hei 6-107563, morpholine derivative, thiomorpholine derivative, etc. in Japanese Provisional Patent Publication No. Hei 6-172178, fluoroalkoxybenzylamine derivative, etc. in Japanese national publication of PCT application No. 6-506473, and spiro[benzo(c)thiophen-1(3H),4′-piperidin]-2-oxide derivative in Japanese Provisional Patent Publication No. Hei 11-43489.
Currently, as a therapeutic agent for the above-mentioned various diseases (especially for emesis, etc.), there have not been discovered yet any compound having an excellent tachykinin receptor antagonistic action (specifically, SP receptor antagonistic action), and at the same time, having sufficiently satisfying safety, sustainability (metabolism, dynamics in vivo) and absorption, etc. Therefore, a compound has been sought for which has a different chemical structure from those of the known tachykinin receptor antagonistic compounds, has an excellent tachykinin receptor antagonistic action, and has sufficiently satisfying clinical effect as the therapeutic agent.
Accordingly, an object of the present invention is to provide a novel compound having excellent tachykinin receptor antagonistic action, and having a clinically satisfying effect in terms of safety, sustainability (metabolism, dynamics in vivo), absorption, etc.